Allergic inflammatory conditions are largely the manifestation of binding of allergen specific IgE to high affinity IgE receptors (FcεRI) on mast cells and basophils. FcεRI cross linking by allergen-IgE complexes results in degranulation and the subsequent release of preformed acute inflammatory mediators (e.g. histamine, tryptase), de novo synthesized arachidonic acid (AA) metabolites (e.g. leukotriene LTC4, prostaglandin D2) and a range of cytokines and chemokines. The acute mediators and AA metabolites result in the early phase allergic response (EAR), characterized by increased vascular permeability, smooth muscle contraction, and the initial influx of inflammatory cells. The late phase allergic response (LAR) is characterized by cytokine- and chemokine-mediated activation and recruitment of additional inflammatory cells (eosinophils, macrophages, T cells). Inhibition of mast cell and basophil degranulation therefore represents an effective approach to the treatment of allergic inflammatory disorders such as asthma, allergic rhinitis, food allergy, allergic conjunctivitis and allergic skin diseases.
Spleen Tyrosine Kinase (SYK) is a non-receptor protein tyrosine kinase of 72 KD, which regulates FcεRI and FcγR signaling in mast cells and basophils and is widely expressed in a variety of inflammatory cells. SYK is upstream of the signaling cascades which regulate calcium flux and gene transcription, and is therefore essential for the production and secretion of both early and late allergic inflammatory mediators in response to allergen-IgE complexes. The critical role of SYK in regulating the degranulatory response is supported by the following observations: (i) SYK−/− murine mast cells fail to produce histamine, LTC4 and TNFα when stimulated through FcεRI; (ii) 10-20% of humans have a “non releaser” basophil phenotype in which these cells fail to degranulate in response to IgE crosslinking; this is due to a cell lineage-restricted and reversible SYK deficiency and (iii) small molecule SYK inhibitors dose-dependently block acute mediator and cytokine release from human mast cells.
There is therefore a need to provide novel inhibitors of SYK which have therapeutic potential in the treatment of allergic conditions and diseases.